Synthesis of many pharmaceuticals, such as aspartyl protease inhibitors, involve the preparation of beta-amino alcohol intermediates from N-protected/N-substituted alpha-amino aldehydes in one or more steps. In particular, pharmaceuticals containing at least one chiral center can be prepared from chiral N-protected/N-substituted alpha-amino aldehydes. Examples of the preparation of chiral N-protected/N-substituted alpha-amino aldehydes and their use as pharmaceutical intermediates in the preparation of aspartyl protease inhibitors, such as renin and HIV protease inhibitors, dietetic sweeteners, bestatin derivatives can be found in Chem. Pharm. Bull. 30:1921-1924, 1982; J. Org. Chem. 43:2480-2482, 1978; J. Org. Chem. 47:3016-3018, 1982; Tet. Let. 27:2337-2340, 1986; PCT/US94/12201; WO 93/23388; WO 94/04491; WO 94/04492;. WO 94/04493; U.S. Pat. No. 4,990,669; Tet. Let. 30:5421-5424, 1989; Philos. Trans. R. Soc. London, A, 326:573-578, 1988; Chem. Rev. 89:149-164, 1989; and J. Org. Chem. 52:2361-2364, 1987. In addition, N-substituted alpha-amino aldehydes are known to have cysteine proteinase inhibition activity, such as papin, calpain and cathepsin inhibition (see for example EP 393457).
A drawback to the use of N-protected/N-substituted alpha-amino aldehydes is their instability to storage, particularly long term storage, (see U.S. Pat. No. 4,990,669; Chem. Rev. 89:149-164, 1989; J. Org. Chem. 47:3016-3018, 1982; and J. Am. Chem. Soc. 109:236-239, 1987). This is particularly true for use of N-protected/N-substituted alpha-amino aldehydes in manufacturing processes, where it is sometimes advantageous to store and ship large quantities of intermediates, such as the N-protected/N-substituted alpha-amino aldehydes, to other locations for processing. Generally, N-protected/N-substituted alpha-amino aldehydes are used promptly following preparation and are not shipped or stored for long periods. Some efforts have been made to form configurationally stable derivatives of N-protected/N-substituted alpha-amino aldehydes (see J. Org. Chem. 52:2361-2364, 1987; and J. Am. Chem. Soc. 109:236-239, 1987), but such derivatives are not always applicable and the aldehyde group may still be unstable to long term storage, for example, due to air oxidation to the corresponding carboxylic acid, trimerization to the corresponding 1,3,5-trioxanes, and the like.